The present disclosure relates to a novel method of preparing hydrogels based on a crosslinked polymer, more particularly that are derived from polysaccharide, and preferably from hyaluronic acid or from one of its salts.
In particular, disclosed is a process that makes it possible to obtain a hydrogel quality that is particularly advantageous for the long-lasting filling of volume defects of the skin.
Hyaluronic acid is known for its viscoelastic properties and also its very great propensity to absorb water. Its properties largely explain the elasticity of the skin. Its biocompatibilities, tolerance and lack of toxicity are such that for more than ten years, this molecule has had applications in medical and cosmetic fields.
Hyaluronic acid is especially used for filling wrinkles.
Wrinkles originate more particularly from a local weakening of the structure of the dermis. Thus, the injection into the dermis of a crosslinked polymer hydrogel at the wrinkles to be treated makes it possible to reduce, or even eliminate the depression of the epidermis. The injections are carried out using pre-filled syringes containing the sterile hydrogel. However, the deepest depressions require relatively viscous gels to be injected.
It is known, generally, that any molecule is much more resistant to degradation and to heat when it is crosslinked. Thus, the advantage of crosslinking hyaluronic acid is known. This crosslinked hyaluronic acid is, in addition, much more stable in the body than the hyaluronic acid molecule. It is also better able to withstand sterilization in an autoclave.
A certain number of processes for preparing crosslinked gels of polymers, or even of polysaccharides, has already been proposed. Generally, these processes require two main steps, the first consists in dissolving the polymer in question in a medium suitable for its homogenization and the second aims to add an agent capable of inducing the crosslinking thereof. Depending on the specific conditions used for the crosslinking, it proves possible to adjust the viscosity or else the rheological properties of the crosslinked hydrogel formed.
By way of illustration of these processes, mention may especially be made of the processes described in US 2006/0105022, which comprises the use of a mixture comprising at least 10% of hyaluronic acid, a crosslinking agent and water under acid or basic conditions, in WO 2006/056204, which comprises a step of treating the hyaluronic acid gel crosslinked with divinyl sulphone and in US 2007/0036745, which results in a cohesive gel starting from a hyaluronan polymer crosslinked with divinyl sulphone (DVS).
However, all of these processes do not give complete satisfaction.
As it emerges from the aforegoing, the crosslinking makes it necessary to first have a homogeneous solution of the starting polymer.
However, putting a polymer, like hyaluronic acid, into solution by dissolving needs to be carried out with gentle agitation, in order to preserve, as best possible, the integrity and the initial size of the polymer chains, of the order of several millions of Daltons in the case of hyaluronic acid. In order to satisfy this constraint, this homogenization step is conventionally carried out under very reduced mechanical agitation and therefore needs to be prolonged in time, for example up to 12 hours which, on an industrial scale, proves prejudicial.
As regards the crosslinking, which conditions the qualities of the final crosslinked hydrogel, it is also important that it be uniform in the gel.
However, the current processes do not make it possible to give a gel an identical degree of crosslinking at any point. Indeed, these processes generally require formulating the polymer within a receptacle, such as pots or tanks (batch) which does not allow a uniform diffusion of the environmental conditions necessary for the crosslinking to take place or the stopping thereof, especially in the case of a static crosslinking. This results in crosslinked gels which may have a relative disparity in terms of degree of crosslinking, this uniformity affecting of course their qualities.
Finally, with regard to the use for which these gels are intended, it is important to ensure that they have irreproachable sanitary qualities. This harmlessness could especially be reinforced by considerably minimizing the contacts of the various media acquired in these processes with the external environment.